Tumor-mediated liver X receptor-alpha activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses.

Abstract

Sterol metabolism has recently been linked to innate and adaptive immune responses through liver X receptor (LXR) signaling. Whether products of sterol metabolism interfere with antitumor responses is currently unknown. Dendritic cells (DCs) initiate immune responses, including antitumor activity after their CC chemokine receptor-7 (CCR7)-dependent migration to lymphoid organs. Here we report that human and mouse tumors produce LXR ligands that inhibit CCR7 expression on maturing DCs and, therefore, their migration to lymphoid organs. In agreement with this observation, we detected CD83(+)CCR7(-) DCs within human tumors. Mice injected with tumors expressing the LXR ligand-inactivating enzyme sulfotransferase 2B1b (SULT2B1b) successfully controlled tumor growth by regaining DC migration to tumor-draining lymph nodes and by developing overt inflammation within tumors. The control of tumor growth was also observed in chimeric mice transplanted with bone marrow from mice lacking the gene encoding LXR-alpha (Nr1h3(-/-) mice) Thus, we show a new mechanism of tumor immunoescape involving products of cholesterol metabolism. The manipulation of this pathway could restore antitumor immunity in individuals with cancer.

• Authors: Eduardo J Villablanca, Laura Raccosta, Dan Zhou, Raffaella Fontana, Daniela Maggioni, Aurora Negro, Francesca Sanvito, Maurilio Ponzoni, Barbara Valentinis, Marco Bregni, Alessandro Prinetti, Knut R Steffensen, Sandro Sonnino, Jan-Ake Gustafsson, Claudio Doglioni, Claudio Bordignon, Catia Traversari, Vincenzo Russo
• Journal: Nature medicine (Nat Med) Vol. 16 Issue 1 Pg. 98-105 (Jan 2010) ISSN: 1546-170X [Electronic] United States
• PMID: 20037595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• CD83 antigen
• Immunoglobulins
• Liver X Receptors
• Membrane Glycoproteins
• NR1H3 protein, human
• Nr1h3 protein, mouse
• Orphan Nuclear Receptors
• Receptors, CCR7

Topics

• Animals
• Antigens, CD (immunology)
• Cell Line, Tumor
• Cell Movement (physiology)
• Dendritic Cells (physiology)
• Gene Expression Regulation (physiology)
• Humans
• Immunoglobulins (immunology)
• Liver X Receptors
• Lymph Nodes (immunology, physiopathology)
• Melanoma (immunology, physiopathology)
• Membrane Glycoproteins (immunology)
• Mice
• Neoplasms, Experimental (immunology, physiopathology)
• Orphan Nuclear Receptors (physiology)
• Receptors, CCR7 (biosynthesis)
• Signal Transduction (physiology)
• Tumor Escape (immunology, physiology)